Substituted 4-Phenylpiperidines for Partial Visual Cycle Inhibition

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Solution Overview

Problem

There is currently no FDA-approved treatment for dry age-related macular degeneration (AMD), a leading cause of blindness, due to excessive accumulation of cytotoxic autofluorescent lipid-protein-retinoid aggregates in the retinal pigment epithelium, which triggers photoreceptor degeneration.

Innovation Solution

Development of substituted 4-phenylpiperidine compounds that inhibit the visual cycle to reduce the formation of cytotoxic bisretinoids like A2E, isoA2E, atRAL di-PE, and A2-DHP-PE, thereby addressing the excessive lipofuscin accumulation in the retina.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Object-affected harmful factors

If the visual cycle is inhibited to reduce bisretinoid formation, then cytotoxic lipofuscin accumulation is reduced, but photoreceptor function may be compromised

Engineering Contradiction:

Improvecytotoxic lipofuscin accumulationVSAvoidphotoreceptor function

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent applies partial inhibition of the visual cycle rather than complete blockade. The compounds inhibit visual cycle enzymes (such as RPE65 or other isoforms) to a degree that reduces bisretinoid formation and lipofuscin accumulation, while maintaining sufficient visual cycle activity to preserve photoreceptor function. This partial action approach allows therapeutic benefit without causing harmful side effects from complete visual cycle suppression.

Inventive Principle:

Principle #16Partial or excessive action

2Adaptability or versatility

If conventional treatments are used for AMD, then other ocular conditions can be treated, but no effective treatment exists for dry AMD specifically

Engineering Contradiction:

Improvetreatment coverage for ocular conditionsVSAvoidefficacy for dry AMD

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent develops compounds with dual functionality: they specifically inhibit the visual cycle to treat dry AMD by reducing lipofuscin accumulation, while also having potential applicability to other ocular conditions involving abnormal retinoid metabolism. The compounds represent a universal therapeutic approach for disorders of the visual cycle, extending beyond just dry AMD to include Stargardt disease and other retinal dystrophies.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The compounds effectively lower serum and retinal concentrations of bisretinoids, providing a potential treatment for dry AMD and other disorders characterized by excessive lipofuscin accumulation, including Stargardt Disease and Best disease.

Implementation Method 1

Development of substituted 4-phenylpiperidine compounds that inhibit the visual cycle to reduce the formation of cytotoxic bisretinoids like A2E, isoA2E, atRAL di-PE, and A2-DHP-PE

Methodology Applied

Scientific EffectVisual cycle inhibition:

Data Source

PatentUS20250320218A1Substituted 4-phenylpiperidines, their preparation and use

Publication Date: 2025.10.16 THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK

AI summary

The present invention provides a compound having the structure:whereinR1, R2, R3, R4, and R5 are each independently H, halogen, CF3 or C1-C4 alkyl,wherein two or more of R1, R2, R3, R4, or R5 are other than H;R6 is H, OH, or halogen; andB is a substituted or unsubstituted heterobicycle,wherein when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other thanor a pharmaceutically acceptable salt thereof.